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Huttenhower, Curtis

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Huttenhower

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Curtis

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Huttenhower, Curtis
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    The Gut Microbiome Modulates the Protective Association Between a Mediterranean Diet and Cardiometabolic Disease Risk
    (Springer Science and Business Media LLC, 2021-02-11) Wang, Dong; Nguyen, Long; Li, Yanping; Yan, Yan; Ma, Wenjie; Rinott, Ehud; Ivey, Kerry; Shai, Iris; Willett, Walter; Hu, Frank; Rimm, Eric; Stampfer, Meir; Chan, Andrew; Huttenhower, Curtis
    Few studies have formally tested the interaction between diet and the gut microbiome in the context of cardiometabolic health, particularly with the microbiome considered as a potential mediator rather than a target of dietary effects. Here, we investigated 307 male participants in the Health Professionals Follow-Up Study who provided up to four stool samples each, yielding 925 shotgun metagenomes and 340 metatranscriptomes, long-term dietary information, and biomarkers of glucose homeostasis, lipid metabolism, and inflammation from blood samples. We demonstrate that a healthy Mediterranean-style dietary pattern is associated with functional and taxonomic components of the gut microbiome, and that its protective associations with cardiometabolic health vary, depending on microbial composition. In particular, the protective association between adherence to the Mediterranean diet and cardiometabolic disease risk was significantly stronger among participants with decreased abundance of Prevotella copri. Our findings represent a step forward in the concept of precision nutrition and have the potential to inform more effective and precise dietary approaches for the prevention of cardiometabolic disease mediated through alterations in the gut microbiome.
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    Growth Effects of N-Acylethanolamines on Gut Bacteria Reflect Altered Bacterial Abundances in Inflammatory Bowel Disease
    (Springer Science and Business Media LLC, 2020-01-20) Fornelos, Nadine; Franzosa, Eric; Bishai, Jason; Annand, John W.; Oka, Akihiko; Lloyd-Price, Jason; Arthur, Timothy D.; Garner, Ashley; Avila-Pacheco, Julian; Haiser, Henry J.; Tolonen, Andrew C.; Porter, Jeffrey A.; Clish, Clary B.; Sartor, R. Balfour; Huttenhower, Curtis; Vlamakis, Hera; Xavier, Ramnik J.; Xavier
    Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analyzed the influences of metabolites that are differentially abundant in IBD on the growth and physiology of gut bacteria that are also differentially abundant in IBD. We found that N-acylethanolamines (NAEs), a class of endogenously-produced signaling lipids elevated in the stool of IBD patients and a T-cell transfer model of colitis, stimulated growth of species overrepresented in IBD and inhibited that of species depleted in IBD in vitro. Using metagenomic sequencing, we recapitulated the effects of NAEs in complex microbial communities ex vivo, with Proteobacteria blooming and Bacteroidetes declining in the presence of NAEs. Metatranscriptomic analysis of the same communities identified components of the respiratory chain as important for the metabolism of NAEs, and this was verified using a mutant deficient for respiratory complex I. In this study, we identified NAEs as a class of metabolites that are elevated in IBD and have the potential to shift gut microbiota toward an IBD-like composition.
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    Multi-Omics of the Gut Microbial Ecosystem in Inflammatory Bowel Diseases
    (Springer Science and Business Media LLC, 2019-05) Lloyd-Price, Jason; Arze, Cesar; Schirmer, Melanie; Andrews, Elizabeth; Ajami, Nadim J.; Brislawn, Colin J.; Courtney, Holly; Gonzalez, Antonio; Graeber, Thomas G.; Hall, A. Brantley; Mallick, Himel; Rahnavard, Gholamali; Sauk, Jenny; Shungin, Dmitry; Vázquez-Baeza, Yoshiki; White, Richard A.; Braun, Jonathan; Denson, Lee A.; Jansson, Janet K.; Knight, Robert; Kugathasan, Subra; McGovern, Dermot P. B.; Stappenbeck, Thaddeus S.; Vlamakis, Hera; Huttenhower, Curtis; Ananthakrishnan, Ashwin; Avila-Pacheco, Julian; Poon, Tiffany; Bonham, Kevin; Casero, David; Lake, Kathleen; Landers, Carol; Plichta, Damian; Prasad, Mahadev; Winter, Harland; Clish, Clary; Franzosa, Eric; Xavier, Ramnik; Petrosino, Joseph
    Inflammatory bowel diseases (IBD), which include Crohn’s disease (CD) and ulcerative colitis (UC), affect several million individuals worldwide. CD and UC are complex diseases and heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Extensive study has focused on individual contributing factors. As part of the Integrative Human Microbiome Project (HMP2), 132 subjects were followed one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each, in total 2,965 stool, biopsy, and blood specimens). These provide a comprehensive view of the gut microbiome’s functional dysbiosis during IBD activity, showing a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (e.g. among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and host serum antibody levels. Disease was also marked by greater temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to the dysregulation. The study’s infrastructure resources, results, and data, available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in IBD.
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    Meeting report for the 1st skin microbiota workshop, boulder, CO October 15-16 2012
    (BioMed Central, 2014) Gilbert, Jack A; Ball, Madeleine; Blainey, Paul; Blaser, Martin J; Bohannan, Brendan JM; Bateman, Ashley; Bunge, John; Dominguez-Bello, Maria Gloria; Epstein, Slava; Fierer, Noah; Gevers, Dirk; Grikscheit, Tracy; Hamdan, Leila J; Harvey, James; Huttenhower, Curtis; Kirkup, Benjamin; Kong, Heidi H; Lauber, Christian; Lemon, Katherine P; Lynch, Susan V; Martin, Lance; Mello, Charlene; Palma, Joseph; Parker, Roy; Petrosino, Joseph; Segre, Julia A; Vosshall, Leslie; Yi, Rui; Knight, Rob
    This report details the outcome of the 1st Skin Microbiota Workshop, Boulder, CO, held on October 15th-16th 2012. The workshop was arranged to bring Department of Defense personnel together with experts in microbial ecology, human skin physiology and anatomy, and computational techniques for interrogating the microbiome to define research frontiers at the intersection of these important areas. The workshop outlined a series of questions and created several working groups to address those questions, specifically to promote interdisciplinary activity and potential future collaboration. The US Army provided generous grant support and the meeting was organized and hosted by the University of Colorado at Boulder. A primary forward vision of the meeting was the importance of understanding skin microbial communities to improve the health and stealth of US Army warfighters.
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    ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial
    (BioMed Central, 2017) Drew, David; Chin, Samantha M.; Gilpin, Katherine K.; Parziale, Melanie; Pond, Emily; Schuck, Madeline M.; Stewart, Kathleen; Flagg, Meaghan; Rawlings, Crystal; Backman, Vadim; Carolan, Peter; Chung, Daniel; Colizzo, Francis; Freedman, Matthew; Gala, Manish; Garber, John; Huttenhower, Curtis; Kedrin, Dmitriy; Khalili, Hamed; Kwon, Douglas S.; Markowitz, Sanford D.; Milne, Ginger L.; Nishioka, Norman; Richter, James; Roy, Hemant K.; Staller, Kyle; Wang, Molin; Chan, Andrew
    Background: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. Methods/design ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1:1:1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. Discussion Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. Trial registration This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02394769. Registered on 16 March 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1744-z) contains supplementary material, which is available to authorized users.
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    A Bayesian method for detecting pairwise associations in compositional data
    (Public Library of Science, 2017) Schwager, Emma; Mallick, Himel; Ventz, Steffen; Huttenhower, Curtis
    Compositional data consist of vectors of proportions normalized to a constant sum from a basis of unobserved counts. The sum constraint makes inference on correlations between unconstrained features challenging due to the information loss from normalization. However, such correlations are of long-standing interest in fields including ecology. We propose a novel Bayesian framework (BAnOCC: Bayesian Analysis of Compositional Covariance) to estimate a sparse precision matrix through a LASSO prior. The resulting posterior, generated by MCMC sampling, allows uncertainty quantification of any function of the precision matrix, including the correlation matrix. We also use a first-order Taylor expansion to approximate the transformation from the unobserved counts to the composition in order to investigate what characteristics of the unobserved counts can make the correlations more or less difficult to infer. On simulated datasets, we show that BAnOCC infers the true network as well as previous methods while offering the advantage of posterior inference. Larger and more realistic simulated datasets further showed that BAnOCC performs well as measured by type I and type II error rates. Finally, we apply BAnOCC to a microbial ecology dataset from the Human Microbiome Project, which in addition to reproducing established ecological results revealed unique, competition-based roles for Proteobacteria in multiple distinct habitats.
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    Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer
    (Nature Publishing Group UK, 2017) Börnigen, Daniela; Ren, Boyu; Pickard, Robert; Li, Jingfeng; Ozer, Enver; Hartmann, Erica M.; Xiao, Weihong; Tickle, Timothy; Rider, Jennifer; Gevers, Dirk; Franzosa, Eric; Davey, Mary Ellen; Gillison, Maura L.; Huttenhower, Curtis
    Oral squamous cell carcinomas are a major cause of morbidity and mortality, and tobacco usage, alcohol consumption, and poor oral hygiene are established risk factors. To date, no large-scale case-control studies have considered the effects of these risk factors on the composition of the oral microbiome, nor microbial community associations with oral cancer. We compared the composition, diversity, and function of the oral microbiomes of 121 oral cancer patients to 242 age- and gender-matched controls using a metagenomic multivariate analysis pipeline. Significant shifts in composition and function of the oral microbiome were observed with poor oral hygiene, tobacco smoking, and oral cancer. Specifically, we observed dramatically altered community composition and function after tooth loss, with smaller alterations in current tobacco smokers, increased production of antioxidants in individuals with periodontitis, and significantly decreased glutamate metabolism metal transport in oral cancer patients. Although the alterations in the oral microbiome of oral cancer patients were significant, they were of substantially lower effect size relative to microbiome shifts after tooth loss. Alterations following tooth loss, itself a major risk factor for oral cancer, are likely a result of severe ecological disruption due to habitat loss but may also contribute to the development of the disease.
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    The healthy human microbiome
    (BioMed Central, 2016) Lloyd-Price, Jason; Abu-Ali, Galeb; Huttenhower, Curtis
    Humans are virtually identical in their genetic makeup, yet the small differences in our DNA give rise to tremendous phenotypic diversity across the human population. By contrast, the metagenome of the human microbiome—the total DNA content of microbes inhabiting our bodies—is quite a bit more variable, with only a third of its constituent genes found in a majority of healthy individuals. Understanding this variability in the “healthy microbiome” has thus been a major challenge in microbiome research, dating back at least to the 1960s, continuing through the Human Microbiome Project and beyond. Cataloguing the necessary and sufficient sets of microbiome features that support health, and the normal ranges of these features in healthy populations, is an essential first step to identifying and correcting microbial configurations that are implicated in disease. Toward this goal, several population-scale studies have documented the ranges and diversity of both taxonomic compositions and functional potentials normally observed in the microbiomes of healthy populations, along with possible driving factors such as geography, diet, and lifestyle. Here, we review several definitions of a ‘healthy microbiome’ that have emerged, the current understanding of the ranges of healthy microbial diversity, and gaps such as the characterization of molecular function and the development of ecological therapies to be addressed in the future.
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    Host genetic variation and its microbiome interactions within the Human Microbiome Project
    (BioMed Central, 2018) Kolde, Raivo; Franzosa, Eric; Rahnavard, Gholamali; Hall, Andrew Brantley; Vlamakis, Hera; Stevens, Christine; Daly, Mark; Xavier, Ramnik; Huttenhower, Curtis
    Background: Despite the increasing recognition that microbial communities within the human body are linked to health, we have an incomplete understanding of the environmental and molecular interactions that shape the composition of these communities. Although host genetic factors play a role in these interactions, these factors have remained relatively unexplored given the requirement for large population-based cohorts in which both genotyping and microbiome characterization have been performed. Methods: We performed whole-genome sequencing of 298 donors from the Human Microbiome Project (HMP) healthy cohort study to accompany existing deep characterization of their microbiomes at various body sites. This analysis yielded an average sequencing depth of 32x, with which we identified 27 million (M) single nucleotide variants and 2.3 M insertions-deletions. Results: Taxonomic composition and functional potential of the microbiome covaried significantly with genetic principal components in the gastrointestinal tract and oral communities, but not in the nares or vaginal microbiota. Example associations included validation of known associations between FUT2 secretor status, as well as a variant conferring hypolactasia near the LCT gene, with Bifidobacterium longum abundance in stool. The associations of microbial features with both high-level genetic attributes and single variants were specific to particular body sites, highlighting the opportunity to find unique genetic mechanisms controlling microbiome properties in the microbial communities from multiple body sites. Conclusions: This study adds deep sequencing of host genomes to the body-wide microbiome sequences already extant from the HMP healthy cohort, creating a unique, versatile, and well-controlled reference for future studies seeking to identify host genetic modulators of the microbiome. Electronic supplementary material The online version of this article (10.1186/s13073-018-0515-8) contains supplementary material, which is available to authorized users.
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    Schrödinger’s microbes: Tools for distinguishing the living from the dead in microbial ecosystems
    (BioMed Central, 2017) Emerson, Joanne B.; Adams, Rachel I.; Román, Clarisse M. Betancourt; Brooks, Brandon; Coil, David A.; Dahlhausen, Katherine; Ganz, Holly H.; Hartmann, Erica M.; Hsu, Tiffany; Justice, Nicholas B.; Paulino-Lima, Ivan G.; Luongo, Julia C.; Lymperopoulou, Despoina S.; Gomez-Silvan, Cinta; Rothschild-Mancinelli, Brooke; Balk, Melike; Huttenhower, Curtis; Nocker, Andreas; Vaishampayan, Parag; Rothschild, Lynn J.
    While often obvious for macroscopic organisms, determining whether a microbe is dead or alive is fraught with complications. Fields such as microbial ecology, environmental health, and medical microbiology each determine how best to assess which members of the microbial community are alive, according to their respective scientific and/or regulatory needs. Many of these fields have gone from studying communities on a bulk level to the fine-scale resolution of microbial populations within consortia. For example, advances in nucleic acid sequencing technologies and downstream bioinformatic analyses have allowed for high-resolution insight into microbial community composition and metabolic potential, yet we know very little about whether such community DNA sequences represent viable microorganisms. In this review, we describe a number of techniques, from microscopy- to molecular-based, that have been used to test for viability (live/dead determination) and/or activity in various contexts, including newer techniques that are compatible with or complementary to downstream nucleic acid sequencing. We describe the compatibility of these viability assessments with high-throughput quantification techniques, including flow cytometry and quantitative PCR (qPCR). Although bacterial viability-linked community characterizations are now feasible in many environments and thus are the focus of this critical review, further methods development is needed for complex environmental samples and to more fully capture the diversity of microbes (e.g., eukaryotic microbes and viruses) and metabolic states (e.g., spores) of microbes in natural environments.